Methods and Apparatus for Treating a Cervix with Ultrasound Energy

ABSTRACT

Methods and apparatuses for speeding the softening of the cervix (cervical ripening) by way of application of ultrasound energy. A vaginal transducer may be used to emit pulse-modulated ultrasound energy directed to the cervix. Focused ultrasound energy may be applied trans-abdominally and directed at the cervix. Ultrasound energy is widely used in medical applications such as diagnostic imaging, therapeutic heating and noninvasive surgery.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 61/735,306 entitled “Methods and Apparatuses forTreating a Cervix With Ultrasound Energy,” filed on Dec. 10, 2012, whichis specifically incorporated herein by reference without disclaimer inits entirety.

BACKGROUND

1. Field of the Invention

This disclosure relates generally to methods and apparatus for thepractice of medical obstetrics. More particularly, this disclosurerelates to methods and apparatus for treating a cervix using ultrasoundenergy.

2. Description of Related Art

Ultrasound energy is widely used in medical applications such asdiagnostic imaging, therapeutic heating and noninvasive surgery.Ultrasound diagnostic imaging employs sound power levels and pulseprotocols considered safe for use in obstetrics. Its long history of usein the clinic supports this conclusion. At much higher ultrasound powerlevels, the vibration of tissue can produce warmth and heating which isuseful in the treatment of soft tissue injuries and certain arthriticconditions. There are also ultrasound based devices that use relativelyhigh intensity focused energy for thermal treatment of cancers.

Ultrasound energy levels used in medical imaging are characterized bytheir mechanical effects where avoidance of cavitation is important andalso by their thermal effects on tissues. The mechanical effects ofultrasound absorption are also known as non-thermal effects and arerepresented by the mechanical index (MI), which is a relative measure.The mechanical index (MI) is defined as the maximal value of the peaknegative pressure of the ultrasound wave measured in milliPascalsdivided by the square root of the acoustic center frequency of theultrasound wave. Regulatory standards in the United States require theMI to be below 1.9 to avoid cavitation. The ultrasound power deliveryknown as I_(SPTA.3) is a derated spatial peak temporal average. Thereare different permissible values of this depending on the target organexposed to ultrasound. The most commonly cited value is 720 m W/cm²I_(SPTA.3) and 190 W/cm² I_(SPPA.3) for exposure to the body (US FDA,Guidance for Industry and FDA Staff: Information for ManufacturersSeeking Marketing Clearance of Diagnostic Ultrasound Systems andTransducers, Document issued on: Sep. 9, 2008). This value is lower fordirect ultrasound exposure of the fetus. Another measure of thermaleffects is the thermal index (TI), which is a calculated estimate oftemperature increase with tissue absorption of ultrasound and is definedas the ratio of the emitted acoustic power to the power required toraise the temperature of tissue by 1° C. Regulatory standards in theUnited States require the TI to be below 1.0.

Ultrasound imaging machines emit microsecond-order pulses into tissuesat a repetition rate that typically does not exceed 4 kHz and thus theduty cycle of the ultrasound energy is relatively low, on the order ofless than one percent. In addition, ultrasound imaging examinations areconducted over short intervals of time, typical minutes, and the overallultrasound integrated dose to a patient is relatively low. Ultrasoundimaging is briefly described below.

Ultrasound imaging (sonography) uses high-frequency sound waves to viewsoft tissues such as muscles and internal organs. Because ultrasoundimages are captured in real-time, they can show movement of the body'sinternal organs as well as blood flowing through blood vessels.

In an ultrasound exam, a hand-held transducer is placed against theskin. The transducer sends out high frequency sound waves that reflectoff of body structures. The returning sound waves, or echoes, aredisplayed as an image on a monitor. The image is based on the frequencyand strength (amplitude) of the sound signal and the time it takes toreturn from the patient to the transducer. Unlike with an x-ray, thereis no ionizing radiation exposure with this procedure.

Ultrasound imaging is used in many types of examinations and procedures.Some examples include:

-   -   a) Doppler ultrasound (to visualize blood flow through a blood        vessel);    -   b) bone sonography (to diagnose osteoporosis);    -   c) echocardiogram (to view the heart);    -   d) fetal ultrasound (to view the fetus in pregnancy);    -   e) ultrasound imaging of the cervix during pregnancy (short        cervix is risk factor for preterm birth)    -   f) ultrasound-guided biopsies; and    -   g) Doppler fetal heart rate monitors (to listen to the fetal        heart beat).

Ultrasound imaging has been used for over 20 years and has an excellentsafety record. It is non-ionizing radiation, so it does not have thesame risks as x-rays or other types of ionizing radiation. Even thoughthere are no known risks of ultrasound imaging, it can produce effectson the body. When ultrasound enters the body, it heats the tissuesslightly. In some cases, it can also produce small pockets of gas inbody fluids or tissues (cavitation). Because of the particular concernfor fetal exposures, national and international organizations haveadvocated prudent use of ultrasound imaging. Furthermore, the use ofdiagnostic ultrasound for non-medical purposes such as fetal keepsakevideos has been discouraged. Ultrasound imaging is used routinely inobstetrics to visualize the cervix in pregnant patients. Transvaginalultrasound imaging has now established that the shorter the sonographiccervical length in the mid-trimester, the higher the risk of pretermdelivery. Indeed, it is possible to assign an individualized risk forpreterm delivery using sonographic cervical length and other maternalrisk factors, such as maternal age, ethnic group, body mass index andprevious cervical surgery. Among these factors, sonographic cervicallength is thought to be one of the most powerful predictors for pretermbirth in the index pregnancy, and is more informative than a history ofprevious preterm birth.

Pulses of longer duration ultrasound, on the order of milliseconds andat repetition rates much lower while still emitting power levels withinMI and I_(SPTA.3) safety limits can produce bioelectrical stimulatoryand in some cases inhibitory effects on the central nervous system. See,e.g., Tyler, W. J., Tufail, Y., Finsterwald, M., Tauchmann, M. L.,Olsen, E. J., Majestic, C., Remote Excitation of Neuronal Circuits UsingLow Intensity, Low Frequency Ultrasound, PLoS One, 3(10):e3511;Bystritsky, A., Korb, A., Douglas, P., Cohen, M., Melega, W.,Mulgaonkar, A., DeSalles, A., Min, B., Yoo, S. S., A Review of LowIntensity Focused Ultrasound Pulsation, Brain Stimulation, vol. 4, no.3, pp. 125-136, (July 2011); Yoo, S. S., Bystritsky, A., Lee, J. H.,Zhang, Y., Fischer, K., Min, B. K., McDannold, N. J., Pascual-Leone, A.,Jolesz, F. A., Focused Ultrasound Modulates Region-Specific BrainActivity, NeuroImage, 56(3), 1267-75, (June 2011)). However, ultrasoundis not known to produce significant effects on the peripheral nervoussystem sufficient to produce action events. See, e.g., Gavrilov L R,Geshuni G V, Il'iniskii O B, Popova L A, Sirotyuk M G, Tsirul'nikov E.M., Stimulation Of Human Peripheral Neural Structures By FocusedUltrasound, Sov Phys Acoust, 19(4):332-334 (1974); Colucci, V.,Strichartz, G., Jolesz, F., Vykhodtseva, N., Hynynen, K., FocusedUltrasound Effects on Nerve Action Potential, Ultrasound in Medicine andBiology, Vol. 35. #10, pp. 1737-1747 (2009). Additionally it is wellknown that ultrasound passes through muscle tissue, even at elevatedpower levels, without producing direct stimulatory effects. There are,however, medical therapeutic applications that would be well served ifultrasound could be applied to the body in a method that would evokephysiologic changes.

The control of events during pregnancy and labor are generallyunderstood to be under hormonal control, but there are certainbioelectrical effects associated with labor and delivery. For example,the underlying electrical activity of the uterine muscle produce thecontractions associated with labor. However, bioelectric events are notthought to be associated with the progress of labor associated withchanges in the cervix and cervical softening. Early changes in tensilestrength during cervical softening result in part from changes in thenumber and type of collagen cross-links and are associated with adecline in expression of two matricellular proteins thrombospondin 2 andtenascin C.

Throughout early pregnancy, the cervix is rigid and thereby helps tomaintain pregnancy by protecting the growing fetus within the uterinecavity. Normally, during the last one-half of pregnancy, the cervixslowly softens in preparation for birth at term. This process isgenerally termed cervical ripening. At term, the softened cervix is thencapable of effacement and dilation to allow the baby to pass through thecervix and vagina during birth. Early cervical ripening often leads topremature birth (i.e., birth of the baby before the 37th week ofgestation) and serious problems related to prematurity. On the otherhand, delay in cervical ripening can result in still birth and seriouslyjeopardize the health of the baby or mother.

Presently, drugs such as prostaglandins and oxytocin are used tostimulate cervical ripening and labor near the end of gestation. It isestimated that about 40 to 60% of pregnant patients are treated withvarious prostaglandin agents to ripen the cervix and prepare patientsfor delivery. Thus, there is a large market for procedures which willripen the cervix effectively. In the year 2000, the total sales forprostaglandins used to ripen the cervix was estimated to be $123 millionin the USA. There are no present estimates but the total market todaycould approach well over $200 million dollars.

Remodeling of the cervix involves enzymatic dissolution of collagenfibrils, increase in water content, and chemical changes. These changesare known to be induced by hormones (estrogen, progesterone, relaxin),as well as cytokines, prostaglandins, and nitric oxide synthesisenzymes.

SUMMARY

According to an exemplary embodiment, a method of promoting cervicalripening comprises applying pulsed ultrasound energy to a cervix at afrequency, pulse duration, pulse repetition rate and peak pulse powersufficient to promote cervical ripening. In certain embodiments, thefrequency range of the ultrasound energy is from 100 kHz to 10 MHz, thepulse duration is in the range of 1-50 milliseconds, the pulserepetition rate is in the range of 10-100 pulses per second, and theinstantaneous peak pulse power (I_(PPP)) is in the range of 10-300W/cm². The average power delivered is less than 720 m W/cm² and theultrasound energy is applied from 10 minutes to 60 minutes.

According to another embodiment, the pulse duration is in the range of10 microseconds to 300 microseconds and delivered in trains of 10-100milliseconds bursts, the repetition rate is 1-25 Hz and the mechanicalindex (MI) is less than or equal to 1.9 and the I_(SPTA.3) is less than720 m W/cm².

In some embodiments, the ultrasound energy is applied to the face of thecervix via an intra-vaginal transducer. Alternatively, the ultrasoundenergy may be applied trans-abdominally to the cervix using a focusedtransducer, wherein the focal zone encompasses the cervix. The focalzone may encompass 60% of the cervix.

In accordance with other embodiments, other treatments, such asprostaglandin or other drugs to promote cervical ripening, may also beused, or ultrasound imaging using high frequency sound waves may be usedto visualize the cervix before or following application of ultrasoundenergy that will soften (ripen) the cervix.

In other embodiments, a method of promoting cervical ripening comprisesapplying ultrasound energy to a cervix, wherein the parameters of theultrasound energy are selected to promote cervical ripening. Theparameters are selected from the group comprising: pulse frequency,pulse duration, pulse repetition frequency, and instantaneous peak pulsepower. The pulsed ultrasound energy may be delivered by directing afocal zone of a focused ultrasound energy transducer towards a cervix orby directing a vaginal transducer towards a cervix.

In certain embodiments, a method of treating a cervix comprises applyingpulsed ultrasound energy to a cervix, wherein a frequency of the pulsedultrasound energy is 100 kHz to 10 MHz, a pulse duration of the pulsedultrasound energy is 1-50 milliseconds; a pulse repetition rate of thepulsed ultrasound energy is 10-100 pulses per second; and a peak pulsepower of the pulsed ultrasound energy is in the range of 10-300 W/cm².The frequency, pulse duration, pulse repetition rate, and peak pulsepower may be selected to promote cervical ripening. The average powerdelivered may be less than 720 m W/cm², and the ultrasound energy may beapplied from 10 minutes to 60 minutes.

In accordance with another embodiment, an apparatus for deliveringultrasound energy comprises an ultrasound transducer and a signalgenerator coupled to the ultrasound transducer to generate ultrasoundenergy. The signal generator is adapted to generate pulsed ultrasoundenergy with a frequency of 100 kHz to 10 MHz, a pulse duration of 1-50milliseconds; a pulse repetition rate of 10-100 pulses per second; and apeak pulse power of 10-300 W/cm².

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1 is a schematic view of an apparatus for applying ultrasoundenergy to a cervix in accordance with an exemplary embodiment;

FIG. 2 is a schematic view of an apparatus used to construct and deliverpulsed ultrasound waveforms;

FIG. 3 is a graph showing focal zone power distribution;

FIG. 4 is an exemplary low frequency ultrasound stimulus waveform;

FIG. 5 is a graph of daily light-induced fluorescence (LIF) measurementduring gestation in treated rats versus control rats;

FIG. 6 is a graph showing changes in LIF after focused ultrasoundapplication as a function of exposure time;

FIG. 7 is a graph showing changes in LIF after focused ultrasoundapplication as a function of power level;

FIG. 8 is a graph showing stretch test results showing the effect ofultrasound on a cervix; and

FIG. 9 is a comparison of fetal delivery weights of ultrasound treatedand control groups.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In the following detailed description, reference is made to theaccompanying drawings, in which are shown exemplary but non-limiting andnon-exhaustive embodiments of the invention. These embodiments aredescribed in sufficient detail to enable those having skill in the artto practice the invention, and it is understood that other embodimentsmay be used, and other changes may be made, without departing from thespirit or scope of the invention. The following detailed description is,therefore, not to be taken in a limiting sense, and the scope of theinvention is defined only by the appended claims.

FIG. 1 shows a system 10 for applying pulsed ultrasound energy which maybe used in accordance with an exemplary embodiment of the presentinvention. The system 10 includes a signal generator 12 which is coupledto a transducer 14 by a cable 16. The transducer 14 may be a focusedtransducer or an intra-vaginal transducer which uses, for example, apiezoelectric transducer to generate mechanical vibrations fromelectrical signals. The signal generator 10 generates a signal to drivethe transducer to generate pulsed ultrasound and may include a powersupply, a function generator, and an oscilloscope to generate andmonitor a signal. The signal generator 10 has controls 18 to adjust theparameters (such as pulse frequency, pulse duration, pulse repetitionfrequency, and instantaneous peak pulse power) of the generated signalin accordance with the values described in further detail below. Thesystem may be compact and implemented as a portable intra-vaginalapplicator. The system may also be incorporated with or implemented by aultrasound imaging system.

In accordance with an exemplary embodiment, ultrasound energy is appliedto a cervix to promote cervical ripening. The ultrasound energy isapplied with a specific pulse protocol that is selected to promotecervical ripening. The power level is comparable to that used inultrasound imaging. However, it differs from ultrasound imaging in thatthe ultrasound pulses are emitted at a lower repetition rate, have alonger duration than used in imaging, and are applied for overall alonger period of time than typical of imaging.

The application of ultrasound is directed so as to apply energy to thecervix while minimizing application of energy to surrounding tissue. Onemethod of doing so is by using a focused ultrasound transducer thatapplies energy through the abdominal wall. The focused ultrasoundtransducer is positioned such that the focal zone encompasses thecervix.

Preferably, at least 60% of the cervix is within the focal zone.However, the positioning of the beam is not critical, as evidenced bythe testing described below. Another method of applying ultrasoundenergy is to use an intra-vaginal device to apply energy at the face ofthe cervix.

In one embodiment, ultrasound at 30-300 W/cm² is applied in the range of1 to 50 millisecond pulses with a pulse repetition rate of 5 to 100 Hzsuch that the overall power level applied to tissue is less than 720 mW/cm² and therefore within generally accepted safe levels of ultrasoundpower. This power level is applied for a suitable duration, such as10-60 minutes. Preferably, the power is applied for approximately 15minutes.

In accordance with another embodiment, ultrasound pulses with arelatively shorter duration, 50 microseconds to 300 microseconds, aredelivered in trains of 10-100 milliseconds bursts. The repetition rateis then 1-25 Hz, which is chosen to maintain an overall safe powerdelivery level. In this embodiment, the shorter duration pulses can usehigher peak power values yet still remain within the range of safe MIand I_(SPTA.3).

Additional therapies may be used in combination with ultrasound topromote the ripening of the cervix. For example, the ultrasoundtreatment may be combined with prostaglandin treatment or other drugs topromote cervical ripening.

The ultrasound ripening technique may also be performed in combinationwith traditional ultrasound imaging (i.e., applying high frequency soundwaves).

EXAMPLE

A study was undertaken to characterize the effect of focused ultrasound(FUS) stimulation on a rat cervix as a means to produce ripening duringpregnancy. Rat models are routinely used in studies of drugs used inhumans for obstetrics and gynaecology applications. Timed-pregnantSprague-Dawley rats (Charles River Laboratories, Wilmington, Mass., USA)were housed separately. The rats were maintained on a constant 12 hourslight and 12 hour dark cycle. The pregnant rats have a 22 day gestationcycle, day 1 being the day on which the sperm plug is observed. Whileundergoing focused ultrasound (FUS) treatment, the animals wereanaesthetized with a combination of xylazine and ketamine based on theirweight 1 μl/g. They were sacrificed by surgical dislocation for cervicaltissue collection.

A custom made ultrasound instrumentation set-up was constructed asillustrated in FIG. 2 to study the effects of FUS on cervix. A functiongenerator 20 (Stanford Research Systems DS-345) provided the excitationwaveform as shown in FIG. 4. An ultrasound power amplifier 22 was builtto drive a transducer 24 made from a 5 cm PZT disk (Steminc Inc.) with afundamental frequency of 0.682 MHz. The transducer was coupled to aspherically focused epoxy (West System Inc.) lens, having a 6.5 cmradius. The FWHM (full width at half maximum) of the output beam wasapproximately 5 mm diameter as measured by hydrophone (PrecisionAcoustics, Devonshire, UK). FIG. 3 shows the focal zone powerdistribution. A thermocouple 26 was used to measure temperature.

The ultrasound energy was applied through a water coupling column andacoustic coupling gel to the rat's abdominal skin surface over thecervix region as determined by palpation of an internal probe placed atthe cervical entrance. The ultrasound beam passed through the annulus ofthe cervix in a parallel incidence to the plane of the cervix.

The experiment tested a range of ultrasound pulse widths at 680 KHzultrasound using 25 Hertz pulse repetition rate as shown in FIG. 4.

As shown in Table 1, the I_(SPPA) used in this experiment was measuredat 40 W/cm² using continuous mode ultrasound and a force balance. TheI_(SPTA) varied from 1 W/cm² to 4 W/cm² by way of pulse durations from 1millisecond to 4 milliseconds. The duration of ultrasound exposure timewas in the range of 30 minutes to 1 hour.

TABLE 1 Day of gestation Stimulation Frequency I_(SPTA) N = number whenapplied time (hour) (KHz) (Watts/cm²) of rats D15 1 — 0 10 D15 1 680 4 9D15 0.5 680 4 2 D14 0.5 — 0 5 D14 0.5 680 4 4 D14 0.5 680 2 4 D14 0.5680 1 4 Total 38

On day 14 or 15 of gestation, a focused ultrasound (FUS) system wasplaced on the abdominal surface of ketamine/xylazine anesthetized ratsat the level of the internal cervix. In control rats, the FUS system wasplaced on the animals but no energy was applied. In treated rats, 680kHz ultrasound at 25 Hertz repetition rate, 2-4 millisecond pulseduration was directed to the cervix from the skin for 0.5 to 1 hour.I_(SPPA.3) was 40 W/cm², which is less than used in imaging (190 W/cm²).The mechanical index (MI) of the ultrasound pulse was calculated to be0.2 and so within safe regulatory limits (1.9).

A light-induced fluorescence (LIF) Collascope (Reproductive ResearchTechnologies Inc., Houston, Tex.) was used to evaluate the changes inthe elasticity of the cervix over time during gestation. LIFmeasurements were made on both experimental and control groups prior toultrasound exposure. One hour after the beginning the FUS ultrasoundtreatment, the LIF test was performed again. LIF measurements were madeon rats every 24 hours until their spontaneous delivery. The average of16 measurements of fluorescent intensity at 390 nm wavelength was usedto evaluate cervical ripening for each animal. Lower numerical valuesrepresent greater cervical ripening. After FUS, the cervix of animalswas examined for mechanical changes and visually by endoscopic camera.Delivery times, fetal weights and fetal viability were made followingdelivery of both control and FUS-treated animals.

The effects of focused ultrasound on the cervix mechanical stretchingand compliance were tested using a universal Tissue Organ Bath System(750TOBS, DMT, Inc.). The cervix is defined as the least vascular tissuewith two parallel lumina between the uterine horns and the vagina.Connective tissue and fat were removed and the cervix was suspended withits longitudinal axis vertically in a tissue bath chamber for tensionrecording. The chamber was filled with physiological Kreb's solution,bubbled with a mixture of 95% 02 and 5% CO2, and maintained at 37° C.The isolated cervix was elongated incrementally at the rate of 0.015mm/s and tension continuously recorded. The slope of the regression linethrough the linear portion of the length-tension curve was employed asan indication of the cervical extensibility. The slope of thelength-tension curve is linearly related to cervical resistance.

Statistical comparisons between two group data were estimated byunpaired student's t-test analysis. A 2-tailed probability value ofP<0.05 was considered to be statistically significant different. Resultsare expressed as means±SEM.

A total of 38 rats were used in the study according to Table 1 where theday of gestation is listed on the left.

FIG. 5 plots the cervical ripening as determined by the LIF forultrasound treated (n=9) animals and for untreated control (n=10)animals and for treatment duration of 1 hour at 4 millisecondsultrasound pulse width. This plot starts at gestation day 15 when FUSstimulation was applied until spontaneously delivery on day 22.

The time of delivery of controls and treated groups were determined ashours after 8 AM of day 22 of gestation. The expulsion of 1 pup wasdefined as delivery. In control animals as seen in FIG. 5 the cervicalLIF values drop with the normal progressive ripening from day 15 ofgestation to day 21.

In the ultrasound treated group LIF values dropped faster from thecontrol value of 2064±116 on day 15 and continued to decline aftertreatment to delivery at 637±133 which is lower than control.

The ultrasound treatment produced LIF values significantly lower(P<0.01) in FUS treated animals on days 16 and 17 that are immediatelyafter ultrasound treatment when compared to controls (day 16: 700±237versus control 1319±241 day 17: 503±231 versus control 1000±178). TheLIF values for the treated group remain low until delivery.

A series of experiments were performed on day 15 for both 30 minute and1 hour at 4 W/cm². After 24 hours and LIF tests, the rat cervix wascollected and mechanical tests of cervical resistance were performed.FIG. 6 shows this result. Ultrasound had a strong cervical ripeningeffect measured at 1 hour after the beginning of stimulation compared tocontrol (1 hour: 806±90, 0.5 hour: 897±99, compared to control:2059±122) and this was sustained over the 24 hour observation interval.The amount of ripening produced by ultrasound at this stage of pregnancywas greater than that of control. Additionally, longer 1 hour exposurescompared to 30 minutes did not appear to produce an additional ripeningeffect. Further testing has shown that ripening is initiated withdurations of 20 minutes, and some trial data suggests 10 minutes may besufficient.

An additional series of experiments were directed to measuring theeffects of power level. This series consisted of 30 minute ultrasoundexposure commencing on day 14 using three different power levels (1W/cm², 2 W/cm², 4 W/cm²). FIG. 7 shows a large and significant cervicalchange (P<0.01) at power levels of 1 W/cm²: 1454±349, 2 W/cm²: 1458±103,4 W/cm²: 1119±89 compared to control of 2467±126 at one hour afterexposure.

FIG. 8 shows the stretch test result for cervical ripening for treatedand control groups. Confirming the result above, there is significantlyincreased cervical extensibility of the ultrasound treated groupcompared to the control group.

FIG. 9 shows that the FUS treated groups have no change in the averageweight (grams) of fetus of control and treated groups (FUS: 5.81±0.43 VSControl: 5.41±0.25). We observed no preterm births in the treated group.All fetuses were delivered within 24 hours after 8 am of day 22.

These studies show that focused ultrasound of the listed pulsecharacteristics produced a significant effect on the rat cervix toproduce early softening or ripening. The physical basis of this effectis unclear and unexpected in view of the scientific literature ofultrasound bioeffects.

The softening of the cervix normally is a gradual and progressiveprocess occurring during the last half of gestation cycle. This findsthat the process of cervical ripening can be substantially acceleratedby application of ultrasound and comparable to a level to animals duringnormal spontaneous that of delivery at term.

In this study 680 kHz ultrasound effects occur after as little as 30minutes exposure and at power levels as low as 1 W/cm². The lowerthreshold of this ultrasound cervical bioeffect was not determined inthis study, and lower values may be satisfactorily used. The effects at4 W/cm² were statistically the same as 1 W/cm² and power levels belowthis were not tested.

By comparison, ultrasound imaging systems typically use 3-6 MHzfrequencies and microsecond-order pulse widths at kilohertz repetitionrate. The difference in pulse characteristics is likely the reason forthe physiologic effects of FUS on cervical ripening since ultrasoundimaging systems are not known to produce physiologic changes.

The largest of the ultrasound induced physiologic change is seen withintens of minutes after stimulation. This is in contrast to the muchslower process of ripening occurring over the last seven to eight daysduring normal pregnancy. The ultrasound induced cervical ripening wasverified by a mechanical stretch test of extensibility.

Experiments show that ultrasound decreased the time course of cervicalripening which was then sustained over the 8 days prior to delivery anddid not reverse back to a rigid state. The induced cervical ripeningappears to be irreversible. We note that the early cervical ripening didnot produce preterm birth or delay birth even though the treated grouphad a cervix soft enough to allow delivery.

The relatively rapid ripening of the cervix by ultrasound is much fasterthan the typical application of prostaglandins that need 12 hours topromote cervical ripening in the clinic with women as is conventionaltreatment. This could be a substantial advantage of the ultrasoundtechnique in that it could be applied clinically to achieve ripeningbefore delivery. The ultrasound energy in these experiments was focusedto the cervix and this would suggest little or no effects on other bodysystems.

Acoustic Intensity Calculation

The pulse characteristics of ultrasound in this study were long comparedto imaging systems but slow in repetition rate. The total ultrasounddose was comparable to imaging systems and to safe regulatoryguidelines. Ultrasound power level is a function of both its intensityand time of application. Spatial-peak pulse-average intensity (I_(sPPA))is defined as:

$I_{SPPA} = \frac{PII}{PD}$

Where PD is the pulse duration defined as (t).

The I_(SPPA) was tested through force balance to be 40 W/cm².Spatial-peak temporal-average intensity (I_(SPTA)) is defined as:

I _(SPTA)=PII(PRF)

Where PRF is pulse repetition frequency, which is represented in Hertz.

The pulse intensity integral (PII) is defined as:

${PII} = {\int{\frac{\rho^{2}(t)}{z_{0}}{t}}}$

Where ρ_(c) is the instantaneous peak pressure, Z₀ is the characteristicacoustic impedance in Pa·s m-1 defined as ρc, where ρ is the density ofthe medium and c is the speed of sound in the medium. ρ was estimated tobe 1028 kg m-3 and c to be 1515 m s-1 for tissue on the basis ofprevious reports. ρ_(r) was calculated to be 158 KPa.

The mechanical index (MI) was calculated by:

${MI} = \frac{\rho \; r}{\sqrt{f}}$

where μ_(r) is the peak rare-factional pressure and f is the acousticfrequency.

From these relationships the I_(SPPA) is calculated at 40 W/cm² whilethe FDA regulatory limit is 190 W/cm² for both the body periphery aswell as the fetus. The mechanical index is calculated at 0.2 and sowithin the FDA limitation of 1.9. FDA regulations define ultrasoundpower levels in terms of power at the target organ I_(SPPA.3) where the0.3 indicates the derated power. Currently the FDA I_(SPTA.3) regulatorylimit on diagnostic imaging systems to organs in the body periphery ispresently 720 m W/cm² (ODRH, 2008). The I_(SPTA.3) was unknown in thisstudy but would be less than 1 W/cm² because of transducer couplinglosses and attenuation of ultrasound as its passes through the tissuesof the rat body.

As recognized by one skilled in the art, there are many variables thatmight be optimized in an effort to achieve lower yet effectiveultrasound power. The lowest effective power is likely to be below thattested in this study since even 1 W/cm² was as effective as the highesttested power at 4 W/cm².

The mechanism of action for ripening of the cervix by the application ofultrasound energy is not generally understood at this time. Withoutbeing bound by any particular theory, it has been postulated that FUSmay include activation of neural and biochemical pathways or directfragmenting collagen X-bridges.

One theory is that ultrasound does not directly affect the collagenousstructure of the cervix but rather triggers a bioelectrical activationthat then causes a cascade of events that affect it indirectly. Anothertheory is that ultrasound may trigger the release of cytokines that thenresult in the ripening process.

Another theory depends on the known stretch sensitivity of the cervix.Mechanical stretching actuates natural physiologic responses and thismay initiate cervical maturation. For example, Takemura et al. (M.Takemural, H. Itoh, N. Sagawa, S. Yura, D. Korita, K. Kakuil, M.Kawamural, N. Hirota, H. Maeda and S. Fujii, “Cyclic mechanical stretchaugments hyaluronan production in cultured human uterine cervicalfibroblast cells”, Molecular Human Reproduction Vol. 11, No. 9 pp.659-665, 2005) report that mechanical stretching of cervical cells inculture causes a biochemical cascade of events that ultimately releaseshyaluron, a biochemical associated with cervical collagen.

Pulses of ultrasound in the repetition range of 5-200 Hz as practiced bythis invention, create a periodic radiation pressure at the pulserepetition rate. Soft tissue at the beam focus is stretched at thispulse rate compared to the ultrasound carrier wave. In the abovedescribed study, for example, the data was generated using a modulationfrequency of 25 Hz. Thus pulsed ultrasound may initiate a cascade ofbiochemical events by way of the stretch sensitivity of cervical tissueand thus promote cervical maturation.

A further theory is that most physiological processes within the bodyhave bioelectrical correlates and processes can be modulated in theirfunction by application of small electrical currents. Ultrasound energyis known to affect bioelectrical events in the CNS and have some effectson the PNS. Thus the observed effects of ultrasound on the cervix may bethrough interaction with a local nerve plexus that then promotes thelocal or more distant release of endogenous prostaglandin.

Furthermore, although bioelectrical events are not known to beassociated with cervical ripening, that there is the possibility andthat the effects of ultrasound could be through a known bioelectricalinteraction with nerves (see, e.g., Gavrilov L R, Geshuni G V,Il'iniskii O B, Popova L A, Sirotyuk M G, Tsirul'nikov E. M. ,Stimulation Of Human Peripheral Neural Structures By Focused Ultrasound,Sov Phys Acoust, 19(4):332-334 (1974); Mihran, R., Barnes, F., Wachtel,H., Temporally Specific Modification of Myelinated Axon ExcitabilityIn-Vitro Following a Single Ultrasound Pulse, Ultrasound in Med. Biol.vol. 16, No. 3., pp. 297-309 (1990); Colucci, V., Strichartz, G.,Jolesz, F., Vykhodtseva, N., Hynynen, K., Focused Ultrasound Effects onNerve Action Potential, Ultrasound in Medicine and Biology, Vol. 35.#10, pp. 1737-1747 (2009)) and these may trigger cervical hormonalrelease.

1. A method of promoting cervical ripening comprising: applying pulsedultrasound energy to a cervix at a frequency, pulse duration, pulserepetition rate and peak pulse power sufficient to promote cervicalripening.
 2. The method according to claim 1, wherein the frequencyrange of the ultrasound energy is 100 kHz to 10 MHz.
 3. The methodaccording to claim 1, wherein the frequency range of the ultrasoundenergy is about 680 kHz.
 4. The method according to claim 1, wherein thepulse duration is in the range of 1-50 milliseconds.
 5. The methodaccording to claim 1, wherein the pulse duration is in the range of 2-10milliseconds.
 6. The method according to claim 1, wherein the pulserepetition rate is within the range of 5-100 pulses per second.
 7. Themethod according to claim 1, wherein the instantaneous peak pulse power(I_(PPP)) is in the range of 10-190 W/cm².
 8. The method according toclaim 1, wherein the instantaneous peak pulse power (I_(PPP)) is about40 W/cm².
 9. The method according to claim 1, wherein the average powerdelivered is less than 720 m W/cm².
 10. The method according to claim 1,wherein the ultrasound energy is applied from 10 minutes to 60 minutes.11. The method according to claim 1, wherein the pulse duration is inthe range of 10 microseconds to 300 microseconds and delivered in trainsof 10-100 milliseconds bursts and the repetition rate is 5-200 Hz; andthe mechanical index (MI) is less than or equal to 1.9 and the Ispta.3is less than 720 m W/cm².
 12. The method according to claim 1, whereinthe ultrasound energy is applied to the face of the cervix via anintra-vaginal transducer.
 13. The method according to claim 1, whereinthe ultrasound energy is applied trans-abdominally using a focusedtransducer, wherein the focal zone encompasses the cervix.
 14. Themethod according to claim 13, wherein 60% of the cervix is within thefocal zone.
 15. The method according to claim 1, wherein the ultrasoundenergy is applied transabdominally using a scanning ultrasound beam soas to progressively cover the cervical area through a process ofcontinuous or interrupted advancement over the tissue volume.
 16. Themethod according to claim 1, further comprising visualizing the cervixby ultrasound applied either transabdominally or vaginally.
 17. Themethod according to claim 1, further comprising treatment withprostaglandin or other drugs to promote cervical ripening.
 18. Themethod of claim 1, further comprising applying high frequency soundwaves for ultrasound imaging.
 19. A method of promoting cervicalripening comprising: applying ultrasound energy to a cervix, wherein theparameters of the ultrasound energy are selected to promote cervicalripening, the parameters being selected from the group comprising: pulsefrequency, pulse duration, pulse repetition frequency, and instantaneouspeak pulse power.
 20. The method of claim 19, wherein the step ofapplying pulsed ultrasound energy comprises directing a focal zone of afocused ultrasound energy transducer towards a cervix.
 21. The method ofclaim 19, wherein the step of applying pulsed ultrasound energycomprises directing a vaginal transducer towards a cervix.
 22. A methodof treating a cervix, comprising: applying pulsed ultrasound energy to acervix, wherein a frequency of the pulsed ultrasound energy is 100 kHzto 10 MHz, a pulse duration of the pulsed ultrasound energy is 1-50milliseconds; a pulse repetition rate of the pulsed ultrasound energy is10-100 pulses per second; and a peak pulse power of the pulsedultrasound energy is in the range of 10-300 W/cm².
 23. The methodaccording to claim 22, wherein the frequency, pulse duration, pulserepetition rate, and peak pulse power promote cervical ripening.
 24. Themethod according to claim 23, wherein the frequency is about 680 kHz,the pulse duration is about 2-4 milliseconds, and the pulse repetitionrate is about 25 Hz.
 25. The method according to claim 22, wherein theaverage power delivered is less than 720 m W/cm².
 26. The methodaccording to claim 22, wherein the ultrasound energy is applied from 10minutes to 60 minutes.
 27. An apparatus for delivering ultrasoundenergy, comprising: an ultrasound transducer; and a signal generatorcoupled to the ultrasound transducer to generate ultrasound energy,wherein the signal generator is adapted to generate pulsed ultrasoundenergy with a frequency of 100 kHz to 10 MHz, a pulse duration of 1-50milliseconds; a pulse repetition rate of 5-100 pulses per second; and apeak pulse power of 10-190 W/cm².